The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB).
There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, the receptors are classified as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells. Thus, the tachykinins are implicated in the pathophysiology and airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions. A cyclopeptide antagonist (FK-224) selective for both NK1 and NK2 receptors has demonstrated clinical efficacy in human patients suffering from asthma and chronic bronchitis. M. Ichinose, et al., Lancet, 1992, 340, 1248.
This invention relates to naphthalenecarboxamide compounds N-substituted by an substituted piperidinylbutyl group, to pharmaceutical compositions containing such compounds, as well as to their uses and processes for their preparation. These compounds antagonize the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 1 (NK1) and the neurokinin 2 (NK2) receptors. These compounds are useful whenever such antagonism is desired. Thus, such compounds are of value in the treatment of those diseases in which Substance P and Neurokinin A are implicated, for example, in the treatment of asthma, anxiety, depression, emesis, urinary incontinence and related conditions.
The N-substituted naphthalenecarboxamide compounds of the present invention show a high degree of both NK1 and/or NK2 receptor antagonist activity. Additionally, by manipulation of the substituents on the naphthalene and piperidine rings of the formula (I), the ratio of activity at the NK1 and NK2 receptors can be modified as desired, affording compounds that are predominantly active at either NK1 or NK2 receptors, or affording compounds with a balanced activity and, as such, are particularly useful when combined antagonism of both receptors is desired. In particular, the compounds of the present invention also possess a high degree of NK1 and/or NK2 antagonism upon oral administration.
Accordingly, the present invention provides the compounds of the general formula (I): 
wherein:
R1, in one respect, has the formula 
wherein R7 is as defined below to give general formula (Ia). 
R2 is hydrogen, hydroxy, C1-6alkoxy, C1-6alkanoyloxy, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, C1-6alkyl, carbamoyl, C1-6alkylcarbamoyl or di-C1-6alkylcarbamoyl.
R3 is hydrogen or C1-6alkyl for example methyl, ethyl, n-propyl or cyclopropyl. Preferably, R3 is methyl.
R4, R5 and R6 are each, independently, hydroxy; cyano; nitro; trifluoromethoxy; trifluoromethyl; C1-6alkylsulfonyl for example methylsulphonyl; halo for example chloro, bromo, fluoro or iodo; C1-6alkoxy for example methoxy, ethoxy or propoxy; C1-6alkyl for example methyl or ethyl; cyanoC1-6alkyl for example cyanomethyl; C2-6alkenyl for example ethenyl, prop-1-enyl or prop-2-enyl; C2-6alkynyl for example ethynyl; carboxy, C1-6alkoxycarbonyl for example methoxycarbonyl; carbamoyl; C1-6alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C1-6alkylcarbamoyl for example di-methylcarbamoyl; C1-6alkanoyl for example acetyl or propionyl; C1-6alkanoylamino for example acetylamino or propionylamino; aminosulfonyl; and substituted C1-6alkyl for example methyl substituted by any of the hereinabove substituents. Additionally, R6 may be hydrogen.
Favourably, R4 is C1-6alkyl for example methyl or ethyl; C1-6alkoxy for example methoxy or ethoxy; or halo for example fluoro, chloro, bromo or iodo. Preferably, R4 is methyl, ethyl, methoxy, ethoxy or fluoro. More preferably, R4 is methoxy or ethyl, most preferably, methoxy.
Preferably, R5 is cyano or nitro; more preferably, R5 is cyano.
Preferably, R6 is hydrogen, methoxy, cyano or nitro.
R7 is xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94.
M is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94.
L is NH or CH2.
The compounds of the present invention possess a number of chiral centres, at xe2x80x94CH(Ph-X1,X2)xe2x80x94, and possibly in the optional substituents (for example the MeSOxe2x80x94 substituent) on either (or both) of the phenyl and naphth-1-yl groups. The present invention covers all isomers, diastereoisomers and mixtures thereof that antagonise NK1 and/or NK2.
The preferred configuration at xe2x80x94CH(Ph-X1,X2)xe2x80x94 is shown in formula (Ib) hereinbelow: 
X1 and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo. Favourably, X1 and X2 are both chloro. In a preferred aspect Ph-X1,X2 is 3,4-dichlorophenyl.
R2 is hydrogen; hydroxy; C1-6alkoxy for example methoxy or ethoxy; C1-6alkanoyloxy for example acetyloxy or propionyloxy; C1-6alkanoyl for example acethyl or propionyl; C1-6alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; C1-6alkanoylamino for example acetylamino; C1-6alkyl for example metrhyl or ethyl; carbamoyl; C1-6alkylcarbamoyI for example methylcarbamoyl or ethylcarbamoyl or di-C1-6alkylcarbamoyl for example dimethylcarbamoyl.
Preferably, R2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. More preferably R2 is hydrogen or methylcarbamoyl.
A preferred class of compounds is that of the formula (II): 
wherein R3 is as hereinbefore defined and R4xe2x80x94R6 are selected from hydrogen, cyano, nitro, methoxy, methyl, ethyl and fluoro.
The most preferred structure is 
Particular compounds of this invention are provided as the Examples hereinbelow. CY-Zalkyl, unless otherwise specified, means an alkyl chain containing a minimum Y total carbon atoms and a maximum Z total carbon atoms. These alkyl chains may be branched or unbranched, cyclic, acyclic or a combination of cyclic and acyclic. For example, the following substituents would be included in the general description xe2x80x9cC4-7alkylxe2x80x9d: 
Pharmaceutically-acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
The compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be used.
Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect the present invention provides a method of treating a disease condition wherein antagonism of the NK1 and/or NK2 receptors is beneficial which comprises administering to a warm-blooded animal an effective amount of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein antagonism of the NK1 and/or NK2 receptors is beneficial.
The compounds of the formula (I) and their pharmaceutically acceptable salts may be made by processes as described and exemplified herein and by processes similar thereto and by processes known in the chemical art. If not commercially available, starting materials for these processes may be made by procedures which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.
In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof which process comprises:
a) reacting a compound of the formula (III) with a compound of the formula (IV): 
wherein R2xe2x80x94R7, L, M, X1 and X2 are as hereinbefore defined; and L and Lxe2x80x2 are groups such that reductive amination of the formulae (III) and (IV) forms a Nxe2x80x94C bond; or
b) reacting a compound of the formula (V) with a compound of the formula (VI): 
wherein R2xe2x80x94R7, L, M, X1 and X2 are as hereinbefore defined; and Lxe2x80x3 is a leaving group;
wherein any other functional group is protected, if necessary, and:
i) removing any protecting groups;
ii) optionally forming a pharmaceutically acceptable salt.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced and removed by conventional methods; see for example Protecting Groups in Organic Chemistry; Theodora W. Greene. Methods of removal are chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
It will also be appreciated that certain of the various optional substituents in the compounds of the formula (I) may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes described hereinabove. The reagents and reaction conditions for such procedures are well known in the chemical art.
The compounds of the formulae (III) and (IV) are reacted under conditions of reductive amination. Typically in the compounds of the formula (III) L is hydrogen.
Typically in the compounds of the formula (IV) Lxe2x80x2 is an oxo group so forming an aldehyde moiety. The reaction is typically performed at a non-extreme temperature, for example 0-100xc2x0 C., suitably ambient temperature in a substantially inert solvent for example dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride.
The compounds of the formula (III) are known or made be prepared in conventional manner. The compounds of the formula (IV) may be prepared, for example, by reacting a compound of the formula (VI) with a compound of the formula (VII): 
wherein Lxe2x80x2, R3, X1 and X2 are as hereinbefore defined under conventional acylation conditions.
The compounds of the formulae (V) and (VI) may be reacted under conventional acylation conditions wherein 
is an acid or an activated acid derivative. Such activated acid derivatives are well known in the literature. They may be formed in situ from the acid or they may be prepared, isolated and subsequently reacted. Typically Lxe2x80x3 is chloro thereby forming the acid chloride. Typically the acylation reaction is performed in the presence of a non-nucleophilic base, for example di-isopropylethylamine, in a substantially inert solvent at a non-extreme temperature.
The compounds of the formula (VII) are known or may be prepared in conventional manner. Certain compounds of the formulae (IV) and (VI) are novel and form part of the present invention. In particular the compounds of the formula (VI) wherein the naphth-1-yl group is substituted by a methoxy group at the 2-position and by a cyano group at the 3-position are novel.
Accordingly, in another aspect the present invention provides a compound of the formula (VIII): 
wherein Lxe2x80x3 is as hereinbefore defined; preferably Lxe2x80x3 is hydrogen or a leaving group such as chloro.
In another aspect the present invention provides a compound of the formulae (IX): 
wherein R3, X1, X2 and Lxe2x80x2 are as hereinbefore defined.
It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the NK1 and NK2 antagonist properties by the standard tests known in the art and those described hereinafter.
Some individual compounds within the scope of this invention may contain double bonds. Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond. Additionally, some species within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.
The following biological test methods, data and Examples serve to illustrate and further describe the invention.
The utility of a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a xe2x80x9ccompoundxe2x80x9d) may be demonstrated by standard tests and clinical studies, including those disclosed in the publications described below.
SP Receptor Binding Assay (Test A)
The ability of a compound of the invention to antagonize the binding of SP at the NK1 receptor may be demonstrated using an assay using the human NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells. The human NK1 receptor was isolated and characterized as described in: B. Hopkins, et al. xe2x80x9cIsolation and characterization of the human lung NK1 receptor cDNAxe2x80x9d Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; and the NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in Test B below.
Neurokinin A (NKA) Receptor Binding Assay (Test B)
The ability of a compound of the invention to antagonize the binding of NKA at the NK2 receptor may be demonstrated using an assay using the human NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, as described in: Aharony, D., et al. xe2x80x9cIsolation and Pharmacological Characterization of a Hampster Neurokinin A Receptor cDNAxe2x80x9d Molecular Pharmacology, 1994, 45, 9-19.
The selectivity of a compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a tissue preparation selective for NK3 receptors. In general, the compounds of the invention which were tested demonstrated statistically significant binding activity in Test A and Test B with a Ki of 1 mM or much less typically being measured.
Rabbit Pulmonary Artery: NK1 in vitro Functional Assay (Test C)
The ability of a compound of the invention to antagonize the action of the agonist Ac-[Arg6, Sar9, Met(O2)11] Substance P (6-11), ASMSP, in a pulmonary tissue may be demonstrated as follows.
Male New Zealand white rabbits are euthanized via i.v. injection into the ear vein with 60 mg/kg Nembutal (50 mg/mL). Preceding the Nembutal into the vein is Heparin (1000 units/mL) at 0.0025 mL/kg for anticoagulant purposes. The chest cavity is opened from the top of the rib cage to the stemum and the heart, lungs and part of the trachea are removed. The pulmonary arteries are isolated from the rest of the tissues and cut in half to serve as pairs.
The segments are suspended between stainless steel stirrups, so as not to remove any of the endothelium, and placed in water-jacketed (37.0xc2x0 C.) tissue baths containing physiological salt solution of the following composition (mM): NaCl, 118.0; KCl, 4.7; CaCl2, 1.8; MgCl2, 0.54; NaH2PO4, 1.0; NaHCO3, 25.0; glucose, 11.0; indomethacin, 0.005 (to inhibit cyclooxygenase); and dl-Propranolol, 0.001 (to block xcex2 receptors); gassed continuously with 95% O2xe2x80x945% CO2. Responses are measured on a Grass polygraph via Grass FT-03 transducers.
Initial tension placed on each tissue is 2 grams, which is maintained throughout the 1.0 hour equilibration period. Tissues are washed with the physiological salt solution at 15 minute intervals. At the 30 and 45 minute wash the following treatments are added: 1xc3x9710xe2x88x926 M Thiorphan (to block E.C.3.4.24.11), 3xc3x9710xe2x88x928M (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide (to block NK2 receptors), and the given concentration of the compound being tested. At the end of the 1.0 h equilibration, 3xc3x9710xe2x88x926M Phenylephrine hydrochloride is added for 1.0 h. At the end of 1.0 h, a dose relaxation curve to ASMSP is done. Each tissue is treated as a individual and is considered finished when it fails to relax further for 2 consecutive doses. When a tissue is complete, 1xc3x9710xe2x88x923M Papaverine is added for maximum relaxation.
Percent inhibition is determined when a tested compound produces a statistically significant (p less than 0.05) reduction of the total relaxation which is calculated using the total relaxation of the Papaverine as 100%. Potencies of the compounds are determined by calculating the apparent dissociation constants (KB) for each concentration tested using the standard equation:
KB=[antagonist]/(dose ratioxe2x88x921)
where dose ratio=antilog[(agonist xe2x88x92log molar EC50 without compound)xe2x88x92(xe2x88x92log molar EC50 with compound)]. The KB values may be converted to the negative logarithms and expressed as xe2x88x92log molar KB (i.e. pKB). For this evaluation, complete concentration-response curves for agonist obtained in the absence and presence of the compound tested using paired pulmonary artery rings. The potency of the agonist is determined at 50% of its own maximum relaxation in each curve. The EC50 values are converted to negative logarithms and expressed as xe2x88x92log molar EC50.
NK2 in vitro Functional Assay (Rest D)
The ability of a compound of the invention to antagonize the action of the agonist [xcex2-ala8] NKA (4-10), BANK, in a pulmonary tissue may be demonstrated as follows. Male New Zealand white rabbits are euthanized via i.v. injection into the ear vein with 60 mg/kg Nembutal (50 mg/mL). Preceding the Nembutal into the vein is Heparin (1000 units/mL) at 0.0025 mL/kg for anticoagulant purposes. The chest cavity is opened from the top of the rib cage to the sternum and a small incision is made into the heart so that the left and right pulmonary arteries can be cannulated with polyethylene tubing (PE260 and PE190 respectively). The pulmonary arteries are isolated from the rest of the tissues, then rubbed over an intimal surface to remove the endothelium, and cut in half to serve as pairs. The segments are suspended between stainless steel stirrups and placed in water-jacketed (37.0xc2x0 C.) tissue baths containing physiological salt solution of the following composition (mM): NaCl, 118.0; KCl, 4.7; CaCl2, 1.8; MgCl2, 0.54; NaH2PO4, 1.0; NaHCO3, 25.0; glucose, 11.0; and indomethacin, 0.005 (to inhibit cyclooxygenase); gassed continuously with 95% O2xe2x80x945% CO2. Responses are measured on a Grass polygraph via Grass FT-03 transducers.
Initial tension placed on each tissue is 2 g, which is maintained throughout the 45 min equilibration period. Tissues are washed with the physiological salt solution at 15 min intervals. After the 45 min equilibration period, 3xc3x9710xe2x88x922M KCl is given for 60 min to test the viability of the tissues. The tissues are then washed extensively for 30 min. The concentration of the compound being tested is then added for 30 min. At the end of the 30 min, a cumulative dose response curve to BANK is performed. Each tissue is treated as a individual and is considered finished when it fails to contract further for 2 consecutive doses. When a tissue is complete, 3xc3x9710xe2x88x922M BaCl2 is added for maximum contraction.
Percent inhibition is determined when a tested compound produces a statistically significant (p less than 0.05) reduction of the total contraction which is calculated using the total contraction of the BaCl2 as 100%. Potencies of the compounds are determined by calculating the apparent dissociation constants (KB) for each concentration tested using the standard equation:
KB=[antagonist]/(dose ratioxe2x88x921)
where dose ratio=antilog[(agonist xe2x88x92log molar EC50 without compound)xe2x88x92(xe2x88x92log molar EC50 with compound)]. The KB values may be converted to the negative logarithms and expressed as xe2x88x92log molar KB (i.e. pKB). For this evaluation, complete concentration-response curves for agonist obtained in the absence and presence of the compound tested using paired pulmonary artery rings. The potency of the agonist is determined at 50% of its own maximum relaxation in each curve. The EC50 values are converted to negative logarithms and expressed as xe2x88x92log molar EC50.
NK1 and NK2 in vivo Functional Assay (Test E)
The activity of a compound as an antagonist of NK1 and/or NK2 receptors also may be demonstrated in vivo in laboratory animals as described in: Buckner et al. xe2x80x9cDifferential Blockade by Tachykinin NK1 and NK2 Receptor Antagonists of Bronchoconstriction Induced by Direct-Acting Agonists and the Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig.xe2x80x9d J. Pharm. Exp. Ther.,1993, Vol 267(3), pp.1168-1175. The assay is carried out as follows.
Compounds are tested in anesthetized guinea pigs pretreated with i.v. indomethacin (10 mg/kg, 20 min), propranolol (0.5 mg/kg, 15 min), and thiorphan (10 mg/kg, 10 min).
Antagonists or vehicle are administered i.v. and orally, 30 and 120 min prior to increasing concentrations of agonist, respectively. The agonists used in these studies are ASMSP (Ac-[Arg6,Sar9,Met(O2)11]-SP(6-11)) and BANK (xcex2-ala-8 NKA4-10).
Administered i.v., ASMSP is selective for NK1 receptors, and BANK is selective for NK2 receptors. Maximum response is defined as zero conductance (GL, 1/Rp). ED50 values are calculated (the dose of agonist resulting in a reduction of GL to 50% of baseline), and converted to the negative logarithm (xe2x88x92logED50). The ED50 values, obtained in the presence (P) and absence (A) of antagonist, are used to calculate a Dose Ratio (P/A), an expression of potency. Data are expressed as meanxc2x1SEM and statistical differences were determined using ANOVA/Tukey-Kramer and Student""s t-test, with p less than 0.05 considered statistically significant.
Compounds of the present invention exhibit marked activity in the foregoing tests and are considered useful for the treatment of those diseases in which the NK1 and/or NK2 receptor is implicated, for example, in the treatment of asthma and related conditions.
Clinical Studies
Clinical studies to demonstrate the efficacy of a compound of the invention may be carried out using standard methods. For example, the ability of a compound to prevent or treat the symptoms of asthma or asthma-like conditions may be demonstrated using a challenge of inhaled cold air or allergen and evaluation by standard pulmonary measurements such as, for example, FEV, (forced expiratory volume in one second) and FVC (forced vital capacity), analyzed by standard methods of statistical analysis.
It will be appreciated that the implications of a compound""s activity in the above described Tests is not limited to asthma, but rather, that the Tests provide evidence of general antagonism of both SP and NKA. SP and NKA have been implicated in the pathology of numerous diseases including: rheumatoid arthritis, Alzheimer""s disease, cancer, schizophrenia, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, anxiety, emesis, Huntington""s disease, psychoses including depression, hypertension, migraine, bladder hypermotility and urticaria.
Accordingly, one feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease in a human or other mammal in need thereof in which SP or NKA is implicated and antagonism of its action is desired.
Asthma is characterized by both chronic inflammation and hyperresponsiveness of the airways. The NK1 receptor is known to mediate inflammation and mucus hypersecretion in airways; and the NK2 receptor is involved in the control of the tone of bronchial smooth muscle. Thus, agents capable of antagonizing the actions of SP and NKA, at the NK1 and NK2 receptors, respectively, are capable of reducing both the chronic inflammation and the airway hyperresponsiveness which are symptomatic of asthma. It has been suggested that an antagonist having mixed affinity for NK1 and NK2 could be therapeutically superior to a receptor selective antagonist. C. M. Maggi xe2x80x9cTachykinin Receptors and Airway Pathophysiologyxe2x80x9d EUR. Respir. J., 1993, 6, 735-742 at 739. Also, it has been suggested that a synergistic effect against bronchoconstriction may result from the simultaneous application of an NK1 antagonist and an NK2 antagonist. D. M. Foulon, et al. xe2x80x9cNK1 and NK2 Receptors Mediated Tachykinin and Resiniferatoxin-induced Bronchospasm in Guinea Pigsxe2x80x9d American Review of Respiratory Disease, 1993, 148, 915-921. Accordingly, another feature of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of asthma in a human or other mammal in need thereof. There is a possible role for Substance P antagonists in the treatment of depression. Accordingly, another feature of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of depression in a human or other mammal in need thereof.
Because of the range of effects attributable to the actions of SP and NKA, compounds which are capable of blocking their actions may also be useful as tools for further evaluating the biological actions of other neurotransmitters in the tachykinin family. As a result, another feature of the invention is provided by the use of a compound of Formula I or a salt thereof as a pharmacological standard for the development and standardisation of new disease models or assays for use in developing new therapeutic agents for treating diseases in which SP or NKA are implicated or for assays for their diagnosis.